The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ASCO 2024 Annual Meeting. Below is a recap of highlighted research presented from Monday, June 3, 2024.
2024 Scientific Highlights
Combination therapy with lenvatinib and pembrolizumab is associated with clinical benefits for advanced renal cell carcinoma across a variety of biomarker subtypes
4504. Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial.
Toni K. Choueiri (Dana Farber Cancer Institute, Boston, MA) reported biomarker analyses from two treatment arms of the phase III CLEAR clinical trial comparing the tyrosine kinase inhibitor lenvatinib combined with the anti-PD-1 immune checkpoint inhibitor pembrolizumab (L+P) to the receptor tyrosine kinase inhibitor sunitinib in treatment-naïve patients with advanced renal cell carcinoma (RCC). In the CLEAR study the L+P arm (n=219) exhibited significant improvement in objective response rate (ORR), progression free survival (PFS), and overall survival (OS) compared to the sunitinib arm (n=222). Baseline levels of PD-L1 expression (n=441; assayed by immunohistochemistry), gene alteration/mutation (n=380; assayed by whole-exome sequencing), or gene expression (n=388; assayed by RNA-seq) were compared between the two treatment arms, and no associations were observed between these baseline characteristics and clinical outcomes. It had been previously shown that P+L was associated with clinical benefit in patients with PD-L1 IHC CPS >=1 and PD-L1 IHC CPS <1, and when PD-L1 IHC (CPS) was analyzed as a continuous variable, PD-L1 levels were not associated with PFS outcomes for the L+P arm (p=0.2301). When patient populations were subdivided based on mutational status of RCC driver genes, PFS consistently favored L+P regardless of gene mutation status. Gene signature scores for T cell inflammation, angiogenesis, proliferation, and MYC were quantified, and none was associated with PFS outcomes for the L+P arm. Angiogenesis and microvessel density signature scores were associated with better PFS outcomes in the sunitinib arm, which validated the analysis since sunitinib inhibits vascular endothelial growth. Proliferation and MYC scores were associated with worse PFS outcomes in the sunitinib arm. L+P was consistently associated with longer PFS than the sunitinib arm across all gene expression signature subgroups. Similar trends were observed in analyses of ORR, with higher ORR associated with L+P vs sunitinib across all subgroups analyzed. L+P was also associated with numerically higher response rates and PFS compared to sunitinib across all tumor molecular subtypes examined. This study indicates that combination therapy of lenvatinib and pembrolizumab provides superior clinical benefit over sunitinib in patients with advanced RCC regardless of biomarker subtypes and has potential to provide positive clinical outcomes in a wide variety of patients with advanced RCC.
Phase I study of RP2, an enhanced oncolytic virus, for metastatic uveal melanoma
9511. Safety, efficacy, and biomarker results from an open-label, multicenter, phase 1 study of RP2 alone or combined with nivolumab in a cohort of patients with uveal melanoma.
Joseph J Sacco (The Clatterbridge Cancer Centre and University of Liverpool, Liverpool, United Kingdom) presented safety, efficacy and biomarker data from a phase I clinical study of RP2 monotherapy and RP2 combined with nivolumab (nivo) for patients with metastatic uveal melanoma (MUM). RP2 is an enhanced-potency oncolytic herpes simplex virus type 1 expressing human granulocyte-macrophage colony-stimulating factor, fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. Unlike cutaneous melanoma, MUM is immunologically “cold” and has a low rate of response to immune checkpoint inhibitors (ICIs). While therapeutic agents like the bispecific antibody tebentafusp have been approved for the treatment of MUM, these agents apply to a select patient population, underscoring an unmet need for a tolerable high-efficacy treatment for patients with MUM. 17 patients with MUM participated in the study. 3 received RP2 monotherapy and 14 combination therapy of RP2 and nivo. 70% of patients had received prior treatment with PD-L1 CTLA-4 ICIs. The overall response rate (ORR) was 29.4% (n=5; 1 in the RP2 monotherapy arm and 4 in the RP2+nivo arm), with all patients achieving partial responses. The disease control rate was 58.8%, and as of the time of data cutoff, the median duration of response was 11.5 months. Translational work is ongoing, but preliminary results indicate that RP2 is associated with robust tumor infiltration of CD8+ T cells in patients who achieved disease control. RP2 is also associated with expansion of T cell clones and new tumor-specific T cells in peripheral blood, although this does not correlate with patient response. 15 patients experienced a treatment-related adverse event (TRAE), but most were manageable, and no grade 4 or 5 TRAEs were observed. These results indicate that RP2 as monotherapy and in combination with nivolumab is associated with durable clinically meaningful responses and a favorable safety profile, providing proof of concept that this modality of treatment could be used to treat ICI-resistant tumors. A larger pivotal study of RP2 is being planned.
Updated results of KEYNOTE-942: Personalized neoantigen vaccine mRNA-4157 plus pembrolizumab for resected melanoma
LBA9512. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.
Jeffrey S. Weber (Perlmutter Cancer Center, NYU Langone Health, New York, NY) presented a 3-year update of the randomized phase 2 KEYNOTE-942 trial investigating mRNA-4157, a novel-mRNA-based individualized neoantigen therapy combined with pembrolizumab (pembro) for completely resected high-risk stage IIIB-IV cutaneous melanoma. Primary analysis of KEYNOTE-942 indicated that at a median follow-up of 23.0 months, mRNA-4157 plus pembro (combination arm; n=107) were associated with prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) compared to standard-of-care pembro monotherapy (pembro arm; n=50). At a median follow-up of 34.9 months, combination treatment continued to be associated with RFS benefit compared to pembro alone (HR 0.51, p=0.019), with 2.5-year RFS rates of 74.8% for the combination arm and 55.6% for the pembro arm. Clinically meaningful improvement in DMFS was also observed (HR 0.384, p=0.0154). 2.5-year DMFS rates of the combination arm and pembro arm differed by over 20 months, at 89.3% and 68.7%, respectively. Overall survival rates also favored the combination arm, and 2.5-year OS rates were 96.0% for the combination arm and 90.2% for the pembro arm (HR 0.425). The RFS benefit associated with the combination arm was maintained in tumor mutation burden- (TMB-) high, TMB-non-high, PD-L1 positive, PD-L1 negative, ctDNA negative, and HLA-heterozygous patient subgroups, suggesting mRNA-4157 plus pembro may benefit a broad patient population. No new safety signals were observed. Combination therapy with the personalized neoantigen vaccine mRNA-4157 and pembrolizumab continues to demonstrate clinically significant benefits in RFS and DMFS and is producing a promising trend in OS regardless of patient biomarker status. A large phase III study of mRNA-4157 and pembrolizumab for completely resected melanoma is currently recruiting patients.
To learn more about a study from Dr. Weber and colleagues on management of immune-related adverse events, read this article by Fa’ak et al in JITC.
OBX-115, an engineered TIL therapy that does not require IL2 for unresectable or advanced melanoma
9515. OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma.
Rodabe Navroze Amaria (Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX) presented data from a first-in-human phase I study to assess the tumor infiltration lymphocyte (TIL) cell therapy OBX-115 in patients with unresectable/metastatic melanoma that is resistant to immune checkpoint inhibitors (ICI). Non-engineered TIL therapy has shown promising activity in treating ICI-resistant metastatic melanoma, but it involves coadministration of high-dose interleukin-2 (IL2). IL-2 treatment which is associated with a large incidence of high-grade toxicities, thus limiting patient eligibility. OBX-115 is an autologous engineered TIL cell therapy that does not require co-administration of IL2 due to inducible and regulatable expression of membrane-bound IL15 (mbIL15). MblIL15 expression is dependent on the FDA-approved small molecule inhibitor acetazolamide (ACZ) which is well-tolerated and can be re-dosed to promote OBX-115 activation and persistence. 10 patients with ICI-resistant advanced or metastatic melanoma received infusion of OBX-115 after lymphodepletion, and 9 of the patients were included in the efficacy analysis. At a median follow-up of 29.5 weeks, no dose-limiting toxicities were observed, and no patients required care at the intensive care unit. No cases of cytokine release syndrome (CRS), neurotoxicity, or capillary leak syndrome were observed, and all hematologic adverse events (AEs) were consistent with known AEs from lymphodepletion. Objective response rate (ORR) was 44.4%, with 2 patients achieving a complete response, 2 patients with a partial response, and 5 patients with stable disease. At a median follow-up of 24 weeks, the progression-free survival rate was 75%. All patients experienced tumor burden reduction, and the disease control rate was 100%. For patients who received 30 billion cells at OBX-115 infusion (n=6), the ORR was 50%. The OBX-115 infusion product was successfully manufactured from tumor tissue from core needle biopsy tumor tissue (n=5) and from surgical incision and exhibited a high proportion of CD8+ stem-like cells and low PD-1 expression. Peripheral blood and tumor biopsies performed after OBX-115 infusion showed NK cell expansion, consistent with trans-presentation of mblIL15 to circulating NK cells. OBX-115, a unique engineered TIL cell therapy that eliminates IL2 from the treatment regimen, exhibits a favorable safety profile and promising clinical efficacy against unresectable or metastatic melanoma. Optimization of the OBX-115 treatment regimen is ongoing in a phase I/II study investigating OBX-115 for advanced melanoma and metastatic non-small cell lung cancer.
To learn about another approach to optimize TIL therapy for melanoma, read this article by Hall et al published in JITC.
T cell receptor-engineered T cell therapy targeting NY-ESO-1 for sarcoma
2500. Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial.
Sandra P. D'Angelo (Memorial Sloan Kettering Cancer Center, New York, NY) presented an interim analysis of IGNYTE-ESO, an ongoing phase II trial of letetresgene autoleucel (lete cel for metastatic or unresectable synovial sarcoma (SyS) or myxoid/round cell liposarcoma (MRCLS). Lete-cel is an autologous engineered T cell receptor (TCR) T cell therapy targeting the NY-ESO-1 cancer testis antigen that is highly expressed in SyS and MRCLS presented by HLA-A*02:01, A*02:05, or A*02:06. Lete-cel has a 12-fold greater binding affinity to NY-ESO-1:HLA complex than naturally occurring TCRs. 73 patients with metastatic NY-ESO-1-positive SyS or MRCLS who were HLA-A*02:01-, *02:05-, or *02:06-positive received lete-cel after lymphodepletion, and 45 patients were evaluable for safety and efficacy analysis. 23 patients (51.5%) received Sys, and 22 patients (48.5%) received MRCLS. The overall response rate (ORR) was 40% (18/45), with 2 patients achieving a complete response (CR) and 16 patients achieving a partial response (PR). ORR among patients with Sys was 39% (9/23, 1 CR and 8 PR), and 41% (9/22) for patients with MRCLS (1 CR and 8 PR). 9 responses were ongoing at the data cutoff, and the median duration of response (DOR) was 10.6 months. All patients experienced adverse events, and 68 patients (93%) experienced grade 3 events. Cytokine release syndrome (CRS) occurred in 63 patients (86%), 9 patients (12%) had grade 3 CRS. ICANS occurred in 3 patients (4%), and all cases were grade 1. These data support the potential of lete-cel as a novel therapy for Sys or MRCLS. Primary analysis of the IGNYTE-ESO will be presented later in 2024, and further analyses of translational correlates are pending.
For a study of the intratumoral microbiome of soft tissue sarcomas, read this article by Perry at al published in JITC.
Efficacy and safety results of REGN7057, a novel stimulatory bispecific antibody for advanced solid tumors
2503. A phase 1/2 study of REGN7075 in combination with cemiplimab (cemi) in patients (pts) with advanced solid tumors: Efficacy and safety results.
Neil Howard Segal (Memorial Sloan Kettering Cancer Center, New York, NY) presented the first report of first in-human phase I/II study of REGN7075, a first-in-class CD28xEGFR costimulatory bispecific antibody (bsAB) for metastatic or locally advanced solid tumors. REGN7075 re-activates and promotes proliferation of T cells at the tumor site through the induction of the CD28 co-stimulatory signal, which enhances the stimulatory interaction of the T cell receptor with MHC-I, thus turning immunologically “cold” tumors “hot.” 94 patients with metastatic or advanced solid tumors who had exhausted standard treatment options received a REGN7075 monotherapy lead-in weekly for a three-week period and then received combination treatment with REGN7075 and the anti-PD-1 immune checkpoint inhibitor cemiplimab every three weeks. 61 patients (65%) had mismatch repair proficient, microsatellite stable colorectal cancer (pMMR/MSS CRC), and efficacy analyses focused on 51 of patients with pMMR/MSS CRC who had received active doses of REGN7075 (100 mg or more). The objective response rate (ORR) of this patient population was 5.9%, with one patient achieving a complete response and 2 patients achieving a partial response. The disease control rate (DCR) was 29.4%. Among the subset of patients with pMMR/MSS CRC who did not have active liver metastases (n=15), ORR was 20.0% and DCR was 80.0%. 82 patients (97.6%) in the safety-evaluable patient population (n=84) experienced a treatment-related adverse event (TRAE), and most TRAEs were grade 1 or 2, and no dose-limiting toxicities were reported. Tumors from responders and non-responders exhibited a range of EGFR expression levels, indicating high baseline levels of EFGR expression is not required for efficacy. Increased serum levels of interferon gamma, indicating T cell activation, was associated with responders. These early data are encouraging, suggesting that REGN7057, a novel EFGRxCD28 costimulatory bispecific antibody, can enhance the anti-tumor immune response and turn immunologically “cold” tumors “hot.” REGN7057 represents the first bispecific antibody for the treatment of pMMR/MSS CRC, which is typically immune refractory. A dose expansion study of REGN7057 for select EGFR-expressing tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, cutaneous squamous cell carcinoma, and CRC has been initiated.
Dostarlimab monotherapy is associated with durable complete responses for mismatch repair deficient advanced rectal cancer
LBA3512. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer.
Andrea Cercek (Memorial Sloan Kettering Cancer Center, New York, NY) reported follow-up from a phase II study of anti-PD-1 immune checkpoint inhibitor dostarlimab for advanced mismatch repair deficient (dMMR) rectal cancer. Previous studies have shown that 6-month treatment with dostarlimab can eliminate dMMR rectal cancers, eliminating the need for surgery or other additional cancer therapy. While these results have led to the incorporation of PD-1 blockade into the standard-of-care neoadjuvant therapy for dMMR rectal cancer, the durability of the response to this treatment is unknown. 48 patients with dMMR rectal cancer participated in the study. 51% of patients tested positive for Lynch Syndrome, and all patients were confirmed to have microsatellite instability-high disease. 42 patients have completed the 6-month course of dostarlimab treatment, and at a median follow-up of 17.9 months, 100% of patients have achieved a complete clinical response (cCR). cCRs have been durable for over 2 years (median follow-up of 26.3 months), and over this 2-year period, no patients have required additional therapy, and no patients experienced a local or distant disease recurrence. Dostarlimab monotherapy is well-tolerated, and no grade 3 or 4 adverse events have been observed. The median time to a cCR was 6.22 months, and the fastest indicator of a cCR was circulating tumor DNA (ctDNA). 97% of patients tested positive for ctDNA at baseline, and clearance was observed in a median of 1.38 months. These results provide further support that dostarlimab monotherapy for dMMR rectal cancer yields durable recurrence-free responses without the need for additional treatment. AZUR1, a global confirmatory study of the long-term efficacy of dostarlimab for dMMR rectal cancer is ongoing.